Addiction Biology最新文献

Studies investigating proteomic associations with alcohol consumption and the genetic links of these proteins to alcohol-related traits are scarce. The aims of our study were (1) to identify proteins associated with alcohol consumption and (2) to investigate the molecular pathways and genetics linking the identified proteins to alcohol consumption and related sociomedical conditions. We generated proteomic and genotypic data from blood samples of 387 Finnish twins (age range: 56–70) and calculated polygenic risk scores (PRSs) of eight alcohol-related traits: obesity, alcohol dependence, number of drinks per week, number of cigarettes per day, major depressive disorders (MDDs), schizophrenia, externalising behaviour and educational attainment. We identified 20 (out of 2321) proteins associated with alcohol consumption, expressed as log ethanol grams per month, after Bonferroni correction and adjustment for BMI, sex and age. Within-pair analyses in monozygotic twin pairs showed that some of the identified associations persisted after accounting for genetic confounding. While only the PRS representing genetic risk for the number of alcoholic drinks per week was associated with alcohol consumption, several proteins were associated with PRSs, in particular the PRS of MDD. All identified proteins were significantly replicated in the UK Biobank, and pathway analysis suggested their collective connection to alcohol consumption might be explained by oxidative stress and cell damage. In conclusion, we identified several alcohol-associated plasma proteins whose levels are also linked to genetic risk for mental illness and substance use. Our study suggests the potential of proteins as biomarkers for early detection of alcohol-related disorders.

Opportunistic interventions (OIs) are health events facilitated by healthcare providers through education that can motivate individuals to adopt risk-reducing behaviours. Our aim was to evaluate transient elastography (TE) as an OI in patients with AUD by assessing changes in validated psychometric scores (PS) of alcohol insight and readiness for change. In this prospective, proof-of-concept pilot study, patients with AUD without TE in the past year were enrolled from an inpatient addiction unit. At baseline, three PS assessing insight and readiness to change were administered: Hanil Alcohol Insight Scale (HAIS), revised Readiness Ruler (RR) and Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES-8A). TE was performed, interpreted, and followed by repeat PS testing. The primary outcome was change in PS. Secondary outcomes were prevalence of fibrosis and steatosis on TE, alcohol use and linkage to hepatology care. From 4 January 2022 to 4 January 2023, 23 patients were enrolled: mean age: 51 years (SD ± 12), 74% male, 61% White and all with severe AUD, and mean of 20 (± 9) daily drinks, 286 g (± 127 g) or 35.7 (± 15.9) units of alcohol, for a median of 14 years (IQR 10–21.5). After TE, there were significant increases in revised RR and SOCRATES-8A from 5 to 8.6 (± 2.1, p < 0.01) and 81.5 to 85.0 (± 8.0, p = 0.04), respectively, indicating improved motivation and readiness for change. HAIS did not change: 11.1–11.0 (± 3, p = 0.36). Cirrhosis and steatosis grade ≥ 2 were detected in 4/23 (17%) and 8/23 (35%), respectively. In this pilot study, performing and interpreting results of TE to inpatients with AUD increase readiness for change and efficiently detects advanced fibrosis.

Cigarette smoking is the single most significant cause of preventable death in the world. Tobacco smoking causes exposure to thousands of chemicals and disrupts biological pathways. It impacts several organs, including the brain, where its effects are mediated by nicotinic acetylcholine receptors. Women seem to be more susceptible to the negative health effects of smoking. In this study, we focused on the changes in the metabolic profile of human postmortem frontal cortex and cerebrospinal fluid (CSF) samples associated with high levels of the nicotine metabolite cotinine. We used non-targeted metabolomics to analyse post-mortem frontal cortex and CSF samples from the Tampere Sudden Death Study cohort. We identified 137 cases (24 females) with high cotinine levels, indicating nicotine exposure. For controls, we identified 82 subjects (20 females) with no cotinine in the frontal cortex or CSF samples and no known history of smoking based on medical records and autopsy reports. Cases had significantly higher levels of 1-methylhistamine (Cohen's d = 0.66, p < 0.0001) and N-acetylputrescine (d = 0.84, p < 0.0001), and lower levels of aspartic acid (d = −0.53, p < 0.001), 3-methylhistidine (d = −0.58, p = 0.0004) and taurine (d = −0.47, p = 0.0002) in the frontal cortex compared to controls. Compared to the frontal cortex, differences between cases and controls were smaller in the CSF samples. Most of the observed differences were similar in both sexes, with a few exceptions like low ergothioneine levels, observed especially in female cases. In conclusion, smoking or nicotine exposure is associated with alterations in metabolites linked to increased oxidative stress and neuroinflammation, as well as reduced neurotransmitter levels in the frontal cortex.

Post-retrieval interventions based on memory reconsolidation have shown promise in reducing addiction-related memories. However, research on methamphetamine (MA) use, particularly in humans, remains limited. This study aimed to evaluate the efficacy of a post-retrieval intervention paradigm in managing methamphetamine use disorder (MUD) with 46 individuals from a compulsory drug rehabilitation centre. A single-blind design was employed, with participants randomly assigned to one of three groups: (1) retrieval–no intervention, (2) retrieval–extinction and (3) retrieval–cognitive task. The study involved baseline testing, followed by memory retrieval using MA cues, and one of the three interventions during the memory reconsolidation window. The interventions were as follows: (1) no further intervention after retrieval, (2) extinction training and (3) playing Tetris after memory reactivation. Relapse was assessed through physiological and psychological indicators, with a focus on both spontaneous and cue-induced relapse of MUD memory. The results showed that both retrieval–extinction and retrieval–cognitive task showed benefits in reducing cravings and preventing relapse in MUD compared to retrieval alone. Physiological and psychological indicators of MA memory relapse showed weak correlation and differed across several dimensions. These findings suggest new strategies for MUD intervention and provide valuable insights for clinical treatment. Limitations of the study are also discussed.

GPR88, an orphan G protein-coupled receptor primarily expressed in the striatum, has emerged as a potential target for treating alcohol use disorder (AUD) due to its role in modulating reward and motivational pathways. In this study, we investigated the effects of the GPR88 agonist RTI-122 on alcohol intake and motivation to self-administer alcohol under different conditions. In mice, RTI-122 reduced alcohol consumption in a two-bottle choice paradigm, which was prevented by Gpr88 knockout, confirming a GPR88-specific effect on the attenuation of alcohol drinking. In rats, RTI-122 dose-dependently reduced operant alcohol self-administration and decreased motivation to self-administer alcohol in progressive ratio tasks, regardless of whether the alcohol was adulterated with quinine or not. Additionally, a high dose of RTI-122 reduced yohimbine-induced reinstatement. Importantly, RTI-122 did not affect water intake in mice or sucrose self-administration in rats, indicating receptor- and reward-specific modulation of alcohol intake. These findings suggest that RTI-122, through GPR88 agonism, effectively reduces alcohol consumption and motivation across various contexts, positioning it as a promising lead for the development of new AUD treatments.

Opioid agonists are known for their effects on the opioid and dopaminergic systems; however, new research points to complementary changes in the gut underlying maladaptive changes associated with opioid use. The gut–brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders, but the spatiotemporal correspondence between quantitative translational measures of gut and brain health is not clear. In this work, we determined longitudinal and concurrent changes in the brain and gut of rodents trained to self-administer morphine for 14 days. Active lever presses delivered a single infusion of morphine (0.4 mg/kg/infusion). We used MRI and 16s rDNA analysis of faecal matter to identify changes from baseline (naïve, nondrug state) to an acute phase (early in the self-administration process, after 2 days of self-administration) and a chronic phase (late in the self-administration process, after 14 days of self-administration). Animals were scanned in a 7T MRI scanner three times (baseline, acute and chronic), and before scanning, faecal matter was collected from each rat. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum and thalamus. We posit that gut changes precede the effects observed in MRI, with the striatum and thalamus emerging as crucial links mediating communication between the gut and the brain.

Substance use disorder constitutes a global health challenge. Preclinical investigations into addiction heavily rely on animal models to explore the underlying biological mechanisms of addictive disorders, with a particular emphasis on understanding the etiological factors influencing drug intake. Exploring sex differences across various phases of addiction has revealed a heightened vulnerability in females. This study systematically reviews the impact of ovarian hormones on the consumption of psychoactive substances in rodents, adhering to the PRISMA 2009 protocol. Our findings underscore the significant role of ovarian hormones, particularly oestrogen, in augmenting drug consumption among female rodents. Notably, with heroin, it was observed that progesterone, rather than oestrogen, facilitated increased consumption in female rodents. The susceptibility to addiction influenced by oestrogen is accentuated across distinct phases, and the molecular mechanisms form a complex interplay that significantly influences addictive behaviours. By bringing together these findings, we aim to establish a strong foundation for future studies. This work may guide clinical investigations in developing more effective prevention or treatment strategies that address the unique vulnerabilities of females to substance use disorders.

A recent study by Hakus et al. (2025) demonstrated sex-associated differences in Pavlovian phenotypes in rodents, with females more likely to exhibit sign-tracking behaviour and males more likely to exhibit goal-tracking behaviour. In the present work, we provide evidence that similar patterns emerge in humans. Using a validated eye-tracking procedure in a Pavlovian learning paradigm, we show that women are more frequently classified as sign-trackers and quantitatively show greater sign-tracking behaviour than men in a large human sample. These results support the translational value of preclinical findings and highlight the importance of considering sex differences in incentive salience attribution. Given the established link between sign-trackers and addiction vulnerability, our findings may help refine our understanding of individual risk factors in the development of such disorders.